The diameter of a needle through which an injectable microparticle suspension is administered can be described in practical terms by both the outer diameter (“OD”) of the needle itself and the inner diameter of the bore or opening inside the needle, which is referred to as the inside diameter (“ID”) of the needle. The inside diameter of the needle must be large enough to permit a microparticle suspension to pass through without the microparticles clogging or otherwise blocking the flow of material through the needle. Additionally, the outside diameter of the needle must be appropriately sized for the particular application.
In the case of parenteral administration of a microparticle suspension, for example administration via a subcutaneous or intramuscular route, the outside diameter of the needle must be appropriately sized to minimize patient pain and discomfort to the extent possible given the clinical, surgical, medical, or pharmaceutical need. In other applications, the outside diameter of the needle must be appropriately sized to facilitate use or administration for the individual application. Often, pharmaceutical applications utilize needles in the range of 19 G to 30 G. “G” refers to the gauge or gauge number of the needle. The smaller the gauge number the larger the diameter of the needle. In other instances, such as infusions, surgical procedures, catheterization procedures, and other medical-device interventions, the outside diameter of the needle (tube) is limited by the equipment that is used to carry out a particular procedure. The needle can also vary in length as well as diameter.
There exists a balance between the inside and outside diameter of a needle that can be used to deliver a microparticle composition in a particular application. The inside diameter must be large enough to make an injection with ease and to avoid clogging, separation of the microparticles from the injection vehicle, failure to administer all microparticle sizes, or other blockages, while at the same time recognizing the need in the marketplace to use smaller-diameter needles to minimize patient pain and discomfort. Typically, smaller-diameter needles offer more versatility and practicality and are less painful to the subject.
Further, for a given size needle, it is desirable to be able to deliver greater quantities of the microparticle composition by administration of suspensions containing a higher solids content of the microparticle composition.
Syringability or injectability refers to the ability of an injectable microparticle suspension to flow through a small-diameter needle or device or, alternatively, for an injectable microparticle suspension to be successfully delivered, injected, or administered through a needle or device having a defined, small-diameter geometry. Several factors affecting injectability, and strategies to improve injectability are described in U.S. Pat. No. 6,667,061 to Ramstack et al.
Various strategies can be used to enhance, preserve, retain, or otherwise improve the injectability of microparticle suspensions. One strategy is to prepare smaller microparticles. Shifting the size range of the microparticle composition to a smaller particle size can improve injectability by simply lowering the potential for aggregates or other blockages in the needle. This approach may also allow for the use of smaller-diameter needles for administration. The use of smaller microparticles can be limiting, however, because smaller microparticles can have different medical or biological properties. For example, small microparticles, particularly those less than 10 microns in size, can be taken up by cells of the immune system (see U.S. Pat. No. 5,942,252 to Tice et al.) causing potentially unintended immunological responses in the subject and/or more rapid clearance by the reticuloendothelial (“RES”) system, thereby decreasing the therapeutic effectiveness of the composition. In cases where cellular uptake is not the intended purpose, it may be undesirable to decrease the size of the microparticles.
Additionally, reducing the particle size of the microparticles can adversely affect the rate of release of the bioactive agent and the time-course, including duration over which the bioactive agent is released from the composition, making the resulting material undesirable for its intended use. For example, reducing the size or diameter of the microparticle can cause a bioactive agent to be released too quickly.
A second strategy that has been used to improve injectability of a microparticle suspension is to modify the properties of the injection vehicle itself. For example, injection vehicles having a high viscosity and a high concentration of surfactants have been used to improve the syringability or injectability of microparticle suspensions. See U.S. Pat. No. 6,667,061 to Ramstack et al. Similarly, U.S. Pat. No. 5,658,593 to Orly et al. describes the use of a viscous biocompatible carrier solution to aid in the injection or administration of a microparticle suspension. Injectable compositions are administered using an injection vehicle containing high concentrations of a viscosity-modifying agent, such as sodium carboxymethyl cellulose (CMC) or other types of polysaccharide viscosity-enhancing agents. However, such viscous compositions have several drawbacks including more pressure required for delivery, and thus more pain for the recipient.
Existing commercial microparticle products require the use of relatively large-diameter needles for their administration or delivery. Commercial pharmaceutical products that are administered as injectable microparticle suspensions include, among others, RISPERDAL® CONSTA® (risperidone), VIVITROL™ (naltrexone), and SANDOSTATIN LAR® (octreotide acetate) which, as indicated in the 2007 Physician's Desk Reference, are administered by 20-gauge thin-wall (20 G-TW), 20-gauge (20 G), and 19-gauge (19 G) needles, respectively, which have outside diameters in the range of about 0.035 inch to 0.042 inch (880-1070 microns) and inside bore diameters in the range of 0.023 inch to 0.0315 inch (580-800 microns). COAPTITE® (Boston Scientific), another microparticle product, is administered through a 21-G needle.
Commercial microparticle compositions, therefore, are typically administered using needles in the size of about 19 G to 21 G. These injectable microparticle compositions typically have particle sizes in the range of about 20-125 microns, with mean particle sizes of about 50-70 microns. The ratios of the inner diameter of the needles (19 G, 20 G, and 20 G-TW with inner diameters of 580-800 microns) to the microparticle diameter (60 microns) for these commercial formulations range from 9.6 to 13.0. Commercial microparticle compositions are typically administered in aqueous vehicles containing a viscosity-modifying agent and/or a surfactant. Suspensions of the microparticle composition in the injection vehicle are typically prepared at a concentration level in the range of about 10-40 wt % (percent solids).
The use of relatively large-diameter (small-gauge) needles, such as those described above, is undesirable to the patient because of pain and discomfort associated with the injection, which can affect patient compliance in maintaining and continuing an overall treatment program, including chronic treatment programs. Further, the aging population continues to support the need for patient care outside of the hospital or clinical settings, such as at-home and hospice (non-clinical) locations. The use of smaller-diameter needles allows administration of microparticle formulations in non-clinical settings by either the patient themselves, family members, or other at-home care-givers. This can improve the quality of life for patients by reducing pain and discomfort, thereby reducing or delaying the need for, frequency of, or duration of, in-patient care.
As a result, there exists a need for microparticle compositions which can be administered through, in relative terms, smaller-diameter needles, and in absolute terms, small diameter needles, without the disadvantages of the current methods of having to reduce the size of the microparticle or rely upon special injection vehicles.
It is therefore an object of the present invention to provide microparticle compositions which can be administered through, in relative terms, smaller-diameter needles, and in absolute terms, small needles, without the disadvantages of the current methods of having to reduce the size of the microparticle or rely upon special injection vehicles, methods of manufacture of such microparticle compositions, and uses thereof.